Compositions and methods for reducing activation of alpha-1 receptors

ABSTRACT

The invention generally relates to compositions and methods for reducing activation of a-1 adrenergic receptors. The compositions comprise highly selective a-2 adrenergic receptor agonists, at low concentrations, such as below 0.05% weight by volume. The compositions preferably comprise brimonidine. The compositions preferably have pH between about 5.5 and about 6.5.

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawing(s) will be provided by thePatent and Trademark Office upon request and payment of the necessaryfee.

BACKGROUND OF THE INVENTION

Dilation of small blood vessels, particularly arterioles, capillaries,and venules, causes many clinically undesirable events including surfacehemorrhage and hyperemia following Lasik surgery, eye redness(conjunctival hyperemia), and nasal congestion (turbinate mucosalswelling secondary to vasodilation).

Adrenergic receptors mediate physiological responses to thecatecholamines, norephinephrine and epinephrine, and are members of thesuperfamily of G protein-coupled receptors having seven transmembranedomains. These receptors, which are divided pharmacologically into a-1,a-2 and β-adrenergic receptor types, are involved in diversephysiological functions including functions of the cardiovascular andcentral nervous systems. The a-adrenergic receptors mediate excitatoryand inhibitory functions: a-1 adrenergic receptors are typicallyexcitatory post-synaptic receptors which generally mediate responses inan effector organ, while a-2 adrenergic receptors are locatedpostsynaptically as well as presynaptically, where they inhibit releaseof neurotransmitters. Agonists of a-2 adrenergic receptors currently areused clinically in the treatment of hypertension, glaucoma, spasticity,and attention-deficit disorder, in the suppression of opiate withdrawal,as adjuncts to general anesthesia and in the treatment of cancer pain.Vascular constriction is known to be mediated by a-adrenergic receptors.

a-2 adrenergic receptors are presently classified into three subtypesbased on their pharmacological and molecular characterization: a-2A/D(a-2A in human and a-2D in rat); a-2B; and a-2C (Bylund et al.,Pharmacol. Rev. 46:121-136 (1994); and Hein and Kobilka, Neuropharmacol.34:357-366 (1995)). The a-2A, a-2B, and a-2C subtypes appear to regulatearterial and/or venular contraction in some vascular beds, and the a-2Aand a-2C subtypes mediate feedback inhibition of norepinephrine releasefrom sympathetic nerve endings. The a-2A subtype also mediates many ofthe central effects of a-2 adrenergic agonists (Calzada and ArtiZano,Pharmacol. Res. 44: 195-208 (2001); Hein et al., Ann. NY Acad. Science881:265-271 (1999); and Ruffolo (Ed.), a-Adrenoreceptors: MolecularBiology, Biochemistry and Pharmacology S. Karger Publisher's Inc.Farmington, Conn. (1991)). The a-2A subtype also mediates potentconstriction of the porcine, but not human, ciliary artery.

Many compounds having selective a-2 agonist activity are known andinclude brimonidine (which has been used for lowering intraocularpressure in patients with open-angle glaucoma or ocular hypertension),guanfacine (which has been used to control high blood pressure),dexmetidomidine (which has been used as a sedative, analgesic,sympatholytic and anxiolytic), and methyl dopa (which has been used as acentrally-acting adrenergic antihypertensive).

The clinically available compounds belong to the general category of aadrenergic receptor agonists. It is a known property of all a adrenergicreceptor agonists, including brimonidine, to cause vasoconstriction.However, known formulations of brimonidine and other known a-2adrenergic receptor agonists are associated with a high incidence ofrebound hyperemia, or other side effects, in clinical use. For example,after as few as three doses of applying known formulations of aadrenergic receptor agonists, patients may develop secondary reboundhyperemia or secondary vasodilation. Brimonidine(5-bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate), a knownselective alpha 2 agonist is associated with significant reboundhyperemia (primary or delayed onset vasodilation) in its currentconcentration range for treating glaucoma of about 0.1% to 0.2%.

Commercially available general alpha agonists for topical mucosaldecongestant use (ophthalmic and nasal applications) includetetrahydrozoline, naphazoline, oxymetazoline, xylometazoline,methoxamine and phenylephrine. These agonists have high alpha 1 receptoragonist activity and are known to cause rebound hyperemia andmedicamentosa. Accordingly, their clinical use is usually restricted toseveral hours or a few days, at most. Many individuals with mucosalcongestion or hyperemia from chronic conditions such as dry eye, contactlens wear, allergic conjunctivitis, allergic rhinitis, nonallergicrhinitis, acute or chronic sinusitis, nasal polyposis, rhinitissecondary to pregnancy, or rhinitis due to nasal septal deviation orobstruction and asthma, particularly, allergic asthma require longerterm agonist use.

To the best of the inventor's knowledge, there are currently no means toinduce effective vasoconstriction without concomitant ischemia caused byan excessive reduction in blood flow and a cascade of inflammatorymediators, resulting in undesirable clinical sequelae of reboundhyperemia, and or medicamentosa, a potentially prolonged inflammatorystate that can last for several weeks or months of rebound mucosalcongestion.

Thus, there is a need for new methods and formulations that wouldprovide safe and long term vasoconstriction with reduced or minimizedside effects, such as rebound hyperemia.

SUMMARY OF THE PRESENT INVENTION

The present invention is generally related to compositions and methodsfor inducing vasoconstriction. One of the key discoveries of the presentinvention lies in using low doses of highly selective a-2 adrenergicreceptor agonists to achieve vasoconstriction with significantly reducedhyperemia.

There are a variety of applications and dosage forms that can beutilized to apply the findings of the invention. For example, someapplications include methods and compositions for: treating nasalcongestion; inducing vasoconstriction; inducing preferentialvasoconstriction of smaller blood vessels relative to larger bloodvessels; reducing capillary permeability in a pulmonary condition;reversing rebound hyperemia; reducing activation of a-1 adrenergicreceptors; and treating and preventing an allergic response with reducedrebound hyperemia.

The invention also encompasses using the compositions and methods ofthis invention for prophylactic reasons, for example, for prophylaxis ofconditions including, but not limited to, asthma, upper respiratorydisease, acute pharyngitis, acute sinusitis, acute tracheobronchitis,influenza, lower respiratory disease, acute bronchitis, bronchiolitis,and community acquired pneumonia (CAP).

The invention also relates to a metered dose dispenser comprising theaqueous compositions of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the variation ofvasoconstriction net clinical effectiveness of prior art compositionscomprising naphazoline, oxymetazoline and tetrahydrozoline at variousconcentrations.

FIG. 2 is a graphical representation of the variation ofvasoconstriction clinical effectiveness of compositions of the presentinvention comprising brimonidine at low concentrations.

FIG. 3 is a graphical representation of clinical effectiveness of thecompositions of the present invention versus prior art compositions.

FIG. 4A is a baseline visual appearance of two eyes of a patient with anocular condition.

FIG. 4B depicts the eyes of the patient 180 minutes after being treatedwith a prior art composition comprising tetrahydrozoline at 0.05% (righteye) and a composition of the present invention comprising brimonidineat 0.01% (left eye);

FIG. 4C depicts the eyes of the patient 240 minutes after baseline (FIG.4A) after being treated with a prior art composition comprisingoxymetazoline at 0.025% (right eye) and a composition of the presentinvention comprising brimonidine at 0.02% (left eye).

FIG. 4D depicts the eyes of the patient 240 minutes after treatmentdescribed in FIG. 4C after being treated with a prior art compositioncomprising naphazoline at 0.033% (right eye) and a composition of thepresent invention comprising brimonidine at 0.02% (left eye).

FIG. 4E depicts the left eye of the patient 240 minutes after treatmentdescribed in FIG. 4D after being treated with a composition of thepresent invention comprising brimonidine at 0.033%.

FIG. 5A is a baseline visual appearance of two eyes of a patient with anocular condition of moderate hyperemia.

FIG. 5B depicts a visual appearance of the right eye of the patientafter being treated with a prior art composition comprising VISINEOriginal® (tetrahydrozoline 0.05%) and the induction of reboundhyperemia, and the visual appearance of the left eye of the patientafter being treated simultaneously with a composition of the presentinvention comprising brimonidine at 0.015%

FIG. 5C depicts a visual appearance of the right eye of the patientafter then being treated with the novel composition of the presentinvention comprising brimonidine at 0.015%, reversing the VISINEOriginal® induced rebound hyperemia, and a visual appearance of the lefteye of the patient after being treated simultaneously with an additionaldrop of the composition of the present invention comprising brimonidineat 0.015%.

FIG. 6 is another graphical representation of clinical effectiveness ofthe compositions of the present invention versus prior art compositions.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For purposes of the present invention, the terms below are defined asfollows.

The term “low concentrations” refers to concentrations from betweenabout 0.0001% to about 0.05%; more preferably, from about 0.001% toabout 0.025%; even more preferably, from about 0.01% to about 0.025%;and even more preferably, from about 0.01% to about 0.02% weight byvolume.

The term “administered locally” refers to administering the compositionsof the present invention approximately at the site where they will comeinto contact with a-2 adrenergic receptors. This term specificallyexcludes oral administration, intravenous injection, or transdermalpatches which are not applied approximately at the spatial location ofthe area which is desired to be treated by the compositions of thepresent invention.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, Alphagan™, andUK14304.

The term “treating” refers to reversing, alleviating, inhibiting, orslowing the progress of the disease, disorder, or condition to whichsuch term applies, or one or more symptoms of such disease, disorder, orcondition.

The term “preventing” refers to prophylactic use to reduce thelikelihood of a disease, disorder, or condition to which such termapplies, or one or more symptoms of such disease, disorder, orcondition. It is not necessary to achieve a 100% likelihood ofprevention; it is sufficient to achieve at least a partial effect ofreducing the risk of acquiring such disease, disorder, or condition.

The term “swollen nasal turbinates condition” includes, but is notlimited to, nasal decongestion.

Vasoconstriction with Reduced Hyperemia

One aspect of the present invention refers to a surprising andunexpected finding that using highly selective a-2 agonists at lowconcentrations allows reducing, minimizing, and/or eliminating reboundhyperemia while optimally providing clinically equal or more effectivevasoconstriction. Rebound hyperemia refers to induced vasodilation(instead of intended vasoconstriction) occurring, often with a lag time,after an application or, more typically, repeated applications ofvasoconstrictors and characterized by engorgement of blood vessels (suchas those in the conjunctiva or nasal mucosa), increased capillarypermeability and leakage, and, in some cases, inflammatory sequelae(medicamentosa), frequently due to the use of an alpha 1 constrictingdrug and particularly, chronic use of a vasoconstricting drug.

Many, if not all, references in the prior art associated reboundhyperemia with all alpha agonists and considered the complication ofrebound hyperemia to be intrinsic to vasoconstriction, wherein bloodflow is reduced, causing attendant ischemia with some inflammatorycascade, precipitating rebound hyperemia in many cases and often leadingto medicamentosa.

Contrary to these teachings, it was surprisingly and unexpectedly foundthat selective alpha-2 (a-2) adrenergic receptor agonists (which arealso interchangeably referred to as “a-2 agonists” throughout theapplication) with extremely high selectivity for a-2 adrenergicreceptors at low concentrations, well below those previouslycontemplated, can induce effective vasoconstriction with low incidenceof rebound hyperemia as compared to the prior art, and low incidence ofallergic reaction, including allergic blepharitis and follicularconjunctivitis. Further, the incidence of ischemia is significantlyreduced through the use of compositions and methods of the presentinvention.

While not wishing to be bound to any particular theory, the inventorbelieves that rebound hyperemia is primarily associated with a-1 agonistactivity. Thus, unless the binding affinity of a-2 agonists for a-2 overa-1 adrenergic receptors is sufficiently high, not sufficiently highlyselective a-2 agonists will cause an undesirable a-1 receptorstimulation with attendant rebound hyperemia. Accordingly, it is desiredto minimize a-1 agonist activity by using highly selective a-2 agonists.

Accordingly, in one embodiment, the invention generally relates to amethod of treating or preventing rebound hyperemia comprisingadministering to a patient in need thereof a selective a-2 adrenergicreceptor agonist having a binding affinity of 100 fold or greater fora-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable saltthereof, wherein said selective a-2 adrenergic receptor agonist ispresent at a concentration below about 0.05% weight by volume.

In another embodiment, the invention relates to a surprising findingthat an aqueous composition comprising a selective a-2 adrenergicreceptor agonist, or a pharmaceutically acceptable salt thereof, can beused for the prevention or treatment of a disease or a condition byadministering said aqueous composition to a patient in need thereof,wherein the concentration of said agonist in said aqueous composition issubstantially lower than the concentration of said agonist normally usedin the treatment of glaucoma.

In another embodiment, the invention generally relates to a compositionfor inducing vasoconstriction comprising a selective a-2 adrenergicreceptor agonist having a binding affinity of 100 fold or greater fora-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable saltthereof, and wherein said selective a-2 adrenergic receptor agonist ispresent at a concentration below about 0.05% weight by volume.

In yet another embodiment, the invention generally relates to acomposition for inducing vasoconstriction comprising a selective a-2adrenergic receptor agonist having a binding affinity of 100 fold orgreater for a-2b and/or a-2c receptors over a-1 adrenergic receptors, ora pharmaceutically acceptable salt thereof, and wherein said selectivea-2 adrenergic receptor agonist is present at a concentration belowabout 0.05% weight by volume.

Further, it was surprisingly and unexpectedly found that selective a-2adrenergic receptor agonists used at a concentration below about 0.05%weight by volume can reverse general/alpha 1 agonist induced hyperemia(instead of causing further ischemia from the induced vasoconstrictionas would be expected for all agonists from prior art teachings), therebyproviding a useful treatment for such patients and possibly alleviatingmedicamentosa from such drug applications, and possibly demonstrating adifferent mechanism of action for vasoconstriction than for alpha 1agonists (FIG. 5 A-C).

In a preferred embodiment, the binding affinity of the selective a-2adrenergic receptor agonist is about 500 fold or greater for a-2 overa-1 adrenergic receptors.

In a preferred embodiment, the selective a-2 adrenergic receptor agonistis present at a concentration between about 0.001% and about 0.025%weight by volume.

In a further preferred embodiment, the selective a-2 adrenergic receptoragonist is selected from the group consisting of apraclonidine,mivazerol, clonidine, brimonidine, alpha methyl dopa, guanfacine,dexemeditomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.

In another preferred embodiment, the composition comprises brimonidineat a concentration between about 0.001% and about 0.025% weight byvolume.

In a more preferred embodiment, a pH of the composition comprising theselective a-2 adrenergic receptor agonist is between about 5.5 and about6.5.

In one embodiment, the invention generally relates to a composition forinducing vasoconstriction consisting essentially of brimonidine, whereinsaid brimonidine concentration is from between about 0.01% to about0.02% weight by volume, wherein pH of said composition is between about5.5 and about 6.5, and wherein said composition is formulated as anocular drop.

In another embodiment, the invention generally relates to a compositionfor inducing vasoconstriction consisting essentially of brimonidine andpotassium, wherein said brimonidine concentration is from between about0.01% to about 0.02% weight by volume, wherein pH of said composition isbetween about 5.5 and about 6.5, and wherein said composition isformulated as an ocular drop.

In the most preferred embodiment, potassium is in the form of potassiumchloride and its concentration is between about 0.2% to about 0.9%weight by volume.

Preferential Vasoconstriction

In one embodiment, methods of the present invention allow to inducepreferential vasoconstriction of smaller blood vessels, such ascapillaries and venules, relative to larger blood vessels, such asarteries and arterioles. These methods reduce activation of a-1adrenergic receptors relative to a-2 adrenergic receptors.

Accordingly, in one embodiment, the invention generally relates to amethod of effectively inducing preferential vasoconstriction ofcapillaries relative to arteries, and/or terminal arterioles,microvessels including capillary beds and/or venules with lower oxygensaturation than larger, proximal higher oxygen saturated arteries and orarterioles, comprising administering to a patient having an ocular orpulmonary condition, a selective a-2 adrenergic receptor agonist havinga binding affinity of 100 fold or greater for a-2 over a-1 adrenergicreceptors, or a pharmaceutically acceptable salt thereof, wherein saidselective a-2 adrenergic receptor agonist is present at a concentrationbelow about 0.05% weight by volume.

By the term “effectively” it is understood that preferentialvasoconstriction results in minimizing and/or eliminating ischemia.

While not wishing to be bound to any particular theory, this methodallows constricting the blood flow to visible surface area with maximalconstriction of microvasculature, together with minimal additionalvasoconstriction of larger arterioles to maximize per unit areavasoconstrictive benefit and minimize ischemic consequence. This can beroughly analogized to reducing water flow at a sprinkler head ratherthan at the connection of the hose leading from the water supply to thesprinkler. Accordingly, this method allows achieving visibly effectivewhitening while optimizing total blood flow by minimizing arteriolarconstriction to produce the best cosmetic and physiologic benefits ofdecongestant activity. Thus, the compositions and methods of the presentinvention make it possible to induce maximal microvessel constrictionwith the least arteriolar constriction.

The method can be used to treat various ocular and pulmonary conditions.In a preferred embodiment, a pulmonary condition may be associated withswollen nasal turbinates. In addition, preferential vasoconstriction ofsmaller blood vessels allows decreasing ischemia, inflammation, rhinitismedicamentosa, and rebound hyperemia.

The invention also relates to compositions formulated for inducingpreferential vasoconstriction.

In one embodiment, a composition for inducing preferentialvasoconstriction of smaller blood vessels relative to larger bloodvessels comprises a selective a-2 adrenergic receptor agonist having abinding affinity of 100 fold or greater for a-2 over a-1 adrenergicreceptors, or a pharmaceutically acceptable salt thereof, wherein saidselective a-2 adrenergic receptor agonist is present at a concentrationbelow about 0.05% weight by volume.

In another preferred embodiment, the method comprises administering to apatient having an ocular condition a composition comprising brimonidine,wherein said brimonidine concentration is between about 0.001% and about0.025% weight by volume.

In a preferred embodiment, the invention generally relates to a methodfor inducing preferential vasoconstriction of smaller blood vesselsrelative to larger blood vessels comprising topically administering to apatient having an ocular condition a composition consisting essentiallyof brimonidine into ocular tissue, wherein pH of said composition isbetween about 5.5 and about 6.5, wherein said brimonidine concentrationis from between about 0.001% to about 0.025% weight by volume andwherein said composition is formulated as an ocular drop.

Thus, in one embodiment, the invention generally relates to acomposition for inducing preferential vasoconstriction consistingessentially of brimonidine into ocular tissue, wherein pH of saidcomposition is between about 5.5 and about 6.5, wherein said brimonidineconcentration is from between about 0.001% to about 0.025% weight byvolume and wherein said composition is formulated as an ocular drop.

In one embodiment, the invention generally relates to administeringcompositions of the present invention within about 24 hours after aLasik surgery on the patient.

In yet another embodiment, the invention generally relates to a methodfor inducing preferential vasoconstriction of smaller blood vesselsrelative to larger blood vessels comprising administering to a patienthaving an ocular or pulmonary condition a selective a-2 agonist having abinding affinity of 100 fold or greater for a-2b and or a-2c receptorsover a-1 adrenergic receptors, or a pharmaceutically acceptable saltthereof, wherein said selective a-2 adrenergic receptor agonist ispresent at a concentration below about 0.05% weight by volume.

Reducing Capillary Permeability

In another embodiment, the invention generally relates to a method ofreducing capillary permeability comprising administering locally to apatient in need thereof a selective a-2 adrenergic receptor agonisthaving a binding affinity of 100 fold or greater for a-2 over a-1adrenergic receptors, or a pharmaceutically acceptable salt thereof, inthe absence of a substantial amount of another therapeutic agent,wherein said selective a-2 adrenergic receptor agonist is present at aconcentration below about 0.05% weight by volume.

In a preferred embodiment, the selective a-2 adrenergic receptor agonistis present at a concentration between about 0.001% and about 0.05%weight by volume.

The method can be used to treat various pulmonary conditions, including,but not limited to, bronchitis, including respiratory syncytial virus(RSV) bronchitis. In a preferred embodiment, a pulmonary condition maybe associated with swollen nasal turbinates. In addition, reducingcapillary permeability allows decreasing ischemia, inflammation,rhinitis medicamentosa, and rebound hyperemia.

The invention also relates to compositions for reducing capillarypermeability. In one embodiment, the invention generally relates to acomposition for reducing capillary permeability comprising administeringto a patient in need thereof a selective a-2 adrenergic receptor agonisthaving a binding affinity of 100 fold or greater for a-2 over a-1adrenergic receptors, or a pharmaceutically acceptable salt thereof,wherein said selective a-2 adrenergic receptor agonist is present at aconcentration below about 0.05% weight by volume.

In one embodiment, the composition for reducing capillary permeabilityconsists essentially of brimonidine, wherein pH of said composition isbetween about 5.0 and about 6.5, wherein said brimonidine concentrationis from between about 0.001% to about 0.025% weight by volume, andwherein said composition is formulated as an aerosolized composition.

In another preferred embodiment, the method comprises administering to apatient in need thereof a composition comprising brimonidine, whereinsaid brimonidine concentration is between about 0.001% and about 0.025%weight by volume. Reducing capillary permeability can be exploited todecrease mucosal swelling and inflammation, such as occurs in thebronchial mucosal lumen of the respiratory tract from a variety ofconditions, including influenza, bacterial pathogens, asthma, allergicasthma, and other causes of mucosal edema of the respiratory tract.

Reducing capillary permeability can also be exploited to decrease spreadof viral and bacterial pathogens, thus potentially reducing the durationand morbidity of various infections, including but not limited to,infections caused by the flu virus.

In addition, reducing capillary permeability allows reducing,alleviating or decreasing ischemia, inflammation, rhinitismedicamentosa, and rebound hyperemia.

Also, reducing capillary permeability allows reducing and/or alleviatingallergic or inflammatory conditions of the respiratory tract associatedwith a pulmonary condition, for example reducing the bronchiole mucosaledema and congestion.

In one embodiment, the invention generally relates to a method ofreducing capillary permeability in a pulmonary condition associated withswollen nasal turbinates comprising administering to a patient in needthereof a composition consisting essentially of brimonidine, wherein pHof said composition is between about 3.5 and about 6.5, wherein saidbrimonidine concentration is from between about 0.001% to about 0.025%weight by volume, and wherein said composition is formulated as anaerosolized composition, and wherein the composition is administeredinto a nasal airway of the patient.

In a preferred embodiment, the invention generally relates to a methodof reducing capillary permeability in a pulmonary condition associatedwith swollen nasal turbinates comprising administering to a patient inneed thereof a composition consisting essentially of brimonidine,wherein pH of said composition is between about 5.0 and about 6.5,wherein said brimonidine concentration is from between about 0.001% toabout 0.025% weight by volume, and wherein said composition isformulated as an aerosolized composition and administered into a nasalairway of the patient.

In another embodiment, the invention generally relates to a method oftreating respiratory syncytial virus (RSV) bronchitis comprisingadministering to a patient in need thereof a composition consistingessentially of brimonidine, wherein pH of said composition is betweenabout 5.0 and about 6.5, wherein said brimonidine concentration is frombetween about 0.001% to about 0.07%, more preferably, from between about0.001% to about 0.03% weight by volume.

In another embodiment, compositions suitable for the methods of thepresent invention can be administered thorough oral ingestion in aboutthe same concentration ranges that are suitable for the topicalapplication.

Reversing Rebound Hyperemia

In one embodiment, the invention generally relates to a method ofreversing rebound hyperemia comprising administering to a patientcurrently or previously undergoing administration of an a-1 adrenergicreceptor agonist a selective a-2 adrenergic receptor agonist having abinding affinity of 100 fold or greater for a-2 over a-1 adrenergicreceptors, or a pharmaceutically acceptable salt thereof, wherein saidfirst selective a-2 adrenergic receptor agonist is present at aconcentration below about 0.05% weight by volume.

By the term “previously undergoing” it is meant the administration (e.g.treatment with) of a-1 agonists that was sufficiently recent to causerebound hyperemia in said patient.

In a preferred embodiment, the selective a-2 adrenergic receptor agonistis present at a concentration from between about 0.001% to about 0.035%weight by volume.

In another preferred embodiment, the method of reversing reboundhyperemia further decreases ischemia, inflammation, and reboundhyperemia associated with a-1 agonist use.

In another preferred embodiment, the invention generally relates to acomposition for reversing rebound hyperemia comprising brimonidine,wherein said brimonidine concentration is between about 0.001% and about0.025% weight by volume.

In a preferred embodiment, the composition further comprises a buffer,and wherein pH of said composition is between about 5.5 and about 6.5.

In another preferred embodiment, the composition for reversing reboundhyperemia consists essentially of brimonidine, wherein said brimonidineconcentration is from between about 0.001% to about 0.025% weight byvolume, wherein pH of said composition is between about 5.5 and about6.5, and wherein said composition is formulated as an ocular drop.

In yet another preferred embodiment, the invention generally relates toa composition for reversing rebound hyperemia consisting essentially ofbrimonidine and a second adrenergic receptor agonist, wherein saidbrimonidine concentration is from between about 0.001% to about 0.025%weight by volume, wherein pH of said composition is between about 5.5and about 6.5, and wherein said composition is formulated as an oculardrop.

Reducing Activation of a-1 Receptors

In another embodiment, the invention generally relates to a method ofreducing activation of a-1 adrenergic receptors comprising administeringto a patient having an ocular or pulmonary condition a selective a-2adrenergic receptor agonist having a binding affinity of 100 fold orgreater for a-2 over a-1 adrenergic receptors, or a pharmaceuticallyacceptable salt thereof, wherein said selective a-2 adrenergic receptoragonist is present at a concentration below about 0.05% weight byvolume.

In a preferred embodiment, the selective a-2 adrenergic receptor agonistis present at a concentration between about 0.001% to about 0.025%weight by volume.

The method can be used to treat various ocular and pulmonary conditions.In a preferred embodiment, a pulmonary condition may be associated withswollen nasal turbinates (e.g., nasal decongestion). In addition,preferential vasoconstriction of smaller blood vessels allows decreasingischemia, inflammation, rhinitis medicamentosa, and rebound hyperemia.

In another preferred embodiment, the method comprises administering to apatient having an ocular condition a composition comprising brimonidine,wherein said brimonidine concentration is between about 0.001% and about0.025% weight by volume.

The invention also encompasses compositions formulated for reducingactivation of a-1 receptors.

In one embodiment, the composition consists essentially of brimonidine,wherein pH of said composition is between about 5.5 and about 6.5,wherein said brimonidine concentration is between about 0.001% and about0.025% weight by volume and wherein said composition is formulated as anocular drop.

In a preferred embodiment, the invention generally relates to a methodof reducing activation of a-1 adrenergic receptors comprising topicallyadministering to a patient having an ocular condition a compositionconsisting essentially of brimonidine into ocular tissue, wherein pH ofsaid composition is between about 5.5 and about 6.5, wherein saidbrimonidine concentration is from between about 0.001% to about 0.025%weight by volume and wherein said composition is formulated as an oculardrop.

In one embodiment, the invention generally relates to administeringcompositions of the present invention within about 24 hours after aLasik surgery on the patient.

In another embodiment, the invention generally relates to a method ofreducing activation of a-1 adrenergic receptors comprising administeringto a patient having a nasal congestion, an ocular or pulmonary conditiona selective a-2 adrenergic receptor agonist having a binding affinity of100 fold or greater for a-2 over a-1 adrenergic receptors, or apharmaceutically acceptable salt thereof, wherein said selective a-2adrenergic receptor agonist is present at a concentration below about0.05% weight by volume, whereby the reduced a-1 adrenergic receptoractivation is below the ED₅₀ for a-1 induced vasoconstriction largerarteries and/or arterioles.

Selective a-2 Adrenergic Receptor Agonists

Selective a-2 agonists that may be used for the purposes of the presentinvention have extremely high selectivity for a-2 adrenergic receptors,defined by their binding affinities (K_(i)) for a-2 over a-1 receptorsof more than 100:1, more preferably 500:1, even more preferably 700:1,even more preferably 1000:1 or greater, and most preferably, 1500:1 orgreater.

It is well within a skill in the art to design an assay to determinea-2/a-1 functional selectivity. As non-limiting examples, potency,activity or EC₅₀ at an a-2A receptor can be determined by assaying forinhibition of adenylate cyclase activity. Furthermore, inhibition ofadenylate cyclase activity can be assayed, without limitation, in PC12cells stably expressing an a-2A receptor such as a human a-2A receptor.As further non-limiting examples, potency, activity or EC₅₀ at an a-1Areceptor can be determined by assaying for intracellular calcium.Intracellular calcium can be assayed, without limitation, in HEK293cells stably expressing an a-1A receptor, such as a bovine a-1Areceptor.

To the best of the inventor's knowledge, and not desiring to be bound byany specific theory or mechanism, it is believed by the inventor thatthe particularly preferred adrenergic receptor agonists for the purposesof the present invention are highly selective for a-2B and/or a-2Creceptors, as opposed to a-2A receptors.

In one embodiment, the selective a-2 adrenergic receptor agonist is acompound which has binding affinity of about 100 fold or greater for a-2over a-1 adrenergic receptors. When a2/a1 is less than about 500 foldbut more than about 100 fold, a concentration of the selective a-2agonist is preferably from about 0.01% to about 0.07%; and is morepreferably from about 0.02% to about 0.04%.

In a preferred embodiment, the selective a-2 adrenergic receptor agonistis a compound which has binding affinity of about 500 fold or greaterfor a-2 over a-1 adrenergic receptors. When a2/a1 is less than about 800fold but more than about 500 fold, a concentration of the selective a-2agonist is preferably from about 0.005% to about 0.05%; and is morepreferably from about 0.01% to about 0.02%.

In a more preferred embodiment, the selective a-2 adrenergic receptoragonist is a compound which has binding affinity of about 700 fold orgreater for a-2 over a-1 adrenergic receptors. When a2/a1 is less thanabout 1200 fold but more than about 800 fold, a concentration of theselective a-2 agonist is preferably from about 0.001% to about 0.025%;and is more preferably from about 0.005% to about 0.01%.

In a more preferred embodiment, the selective a-2 adrenergic receptoragonist is a compound which has binding affinity of about 1000 fold orgreater for a-2 over a-1 adrenergic receptors. When a2/a1 is less thanabout 2000 fold but more than about 1200 fold, a concentration of theselective a-2 agonist is preferably from about 0.0005% to about 0.01%;and is more preferably from about 0.0025% to about 0.005%.

In a more preferred embodiment, the selective a-2 adrenergic receptoragonist is a compound which has binding affinity of about 1500 fold orgreater for a-2 over a-1 adrenergic receptors. When a2/a1 is more thanabout 2000 fold, a concentration of the selective a-2 agonist ispreferably from about 0.0002% to about 0.005%; and is more preferablyfrom about 0.001% to about 0.003%.

The selective a-2 adrenergic receptor agonist may be present at aconcentration from between about 0.0001% to about 0.05%; morepreferably, from about 0.001% to about 0.025%; even more preferably,from about 0.01% to about 0.025%; and even more preferably, from about0.01% to about 0.02% weight by volume.

It is preferred that a concentration of a selective a-2 adrenergicreceptor agonist be below its vasoconstriction vs. concentrationplateau. Typically, the optimal concentration is 10% to 90% above theminimal threshold of measurable vasoconstriction for a particular a-2agonist, or below that of the plateau maximum concentration, and ispreferably within the about 25% to about 75% range of either of thesebenchmarks. The term “plateau maximum concentration” means theconcentration above which there is no or minimal furthervasoconstriction effect. Other considerations in choosing a selectivea-2 adrenergic receptor agonist are blood brain permeability and anypossible side effects and other systemic reactions.

In one embodiment, the selective a-2 adrenergic receptor is selectedfrom the group consisting of apraclonidine, mivazerol, clonidine,brimonidine, alpha methyl dopa, guanfacine, dexemeditomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.Analogs of these compounds that function as highly selective a-2agonists may also be used in compositions and methods of the presentinvention.

In a more preferred embodiment, the selective a-2 adrenergic receptor isbrimonidine in the form of tartrate salt.

Methods of Treatment and Compositions Thereto

The surprising and unexpected discoveries of the present inventionpotentially have application in treating a nasal congestion and avariety of ocular and pulmonary conditions.

a) Swollen Nasal Turbinates (e.g., Nasal Congestion)

Thus, in one embodiment, the invention generally relates to a method oftreating diseases associated with swollen nasal turbinates (e.g. nasalcongestion), comprising administering locally to a patient in needthereof a selective a-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for a-2 over a-1 adrenergic receptors,or a pharmaceutically acceptable salt thereof, wherein said selectivea-2 adrenergic receptor agonist is present at a concentration belowabout 0.05% weight by volume.

In a preferred embodiment, the condition associated with swollen nasalturbinates is selected from the group consisting of nasal congestion,allergic rhinitis, asthma, sleep disorders, and sleep apnea.

In one embodiment, the invention generally relates to compositionsformulated for treating diseases associated with swollen nasalturbinates. Compositions particularly useful for these purposespreferably comprise brimonidine at concentrations of from 0.01% to about0.04%, and more preferably, from 0.02% to about 0.035%.

b) Ocular Conditions

Ocular conditions include, but are not limited to, red eye, includingchronic red eye; ocular vascular congestion after Lasik surgery;prophylactic intraoperative and postoperative reduction of hemorrhageand hyperemia after Lasik surgery; preoperative hemorrhage and hyperemiaprophylaxis prior to Lasik surgery; prophylactic diabetic retinopathy;macular edema such as that associated with diabetes; conditions ofretinal degeneration such as glaucoma, macular degeneration such asage-related macular degeneration (ARMD) and retinitis pigmentosa;retinal dystrophies; elevated baseline hyperemia in glaucoma patients;inflammatory disorders of the retina; vascular occlusive conditions ofthe retina such as retinal vein occlusions or branch or central retinalartery occlusions; retinopathy of prematurity; retinopathy associatedwith blood disorders such as sickle cell anemia; elevated intraocularpressure; ocular itch; damage following retinal detachment; damage orinsult due to vitrectomy, retinal or other surgery; and other retinaldamage including therapeutic damage such as that resulting from lasertreatment of the retina, for example, pan-retinal photocoagulation fordiabetic retinopathy or photodynamic therapy of the retina. Ocularconditions that can be prevented or alleviated by administering thetopical formulations of the present invention further include, withoutlimitation, generic and acquired optic neuropathies such as opticneuropathies characterized primarily by loss of central vision, forexample, Leber's hereditary optic neuropathy (LEON), autosomal dominantoptic atrophy (Kjer disease) and other optic neuropathies such as thoseinvolving mitochondrial defects aberrant dynamin-related proteins orinappropriate apoptosis; and optic neuritis such as that associated withmultiple sclerosis, retinal vein occlusions or photodynamic or lasertherapy. See, for example, Carelli et al., Neurochem. Intl. 40:573-584(2002); and Olichon et al., J. Biol. Chem. 278:7743-7746 (2003). Theterm “ocular condition” also encompasses aesthetic conditions, forexample, excessive redness of an eye. The methods and compositions ofthe present invention can be used with other ocular procedures,particularly cataract surgery, retinal surgery, pterygiae removal, andmotility surgery. At the concentration range employed to eliminatehyperemia, endothelial cell pump dysfunction, and the high level ofallergic reactions of the glaucoma class of brimonidine concentrations,no intraocular pressure effects are noted. This is important because incosmetic use, while retention of normal intraocular pressure is desired,lowering of intraocular pressure is not a necessary or desirableparameter to reduce in a normotensive population.

When the methods and compositions of the present invention are used inconjunction with Lasik surgery, the preferred a-2 agonist is brimonidineat a concentration of from about 0.015% to about 0.05%, and morepreferably, from about 0.020% to about 0.025%. In a preferredembodiment, a selective a-2 agonist's concentration has to be such thatintraocular pressure is not substantially reduced and endothelial cellpump is not substantially inhibited.

It is a further discovery of the present invention that the doseresponse curve for intraocular pressure reduction for brimonidine issignificantly different than that for its vasoconstrictive effects, aswell as endothelial cell pump inhibition. Despite brimonidine having thesame hyperemic profile and high incidence of rebound hyperemia inclinical use as apraclonidine, when this class of more selectivecompounds is optimized to its vasoconstrictive dose response range, itis shown to have superior vasoconstrictive effect with less rebound(See, FIG. 3).

c) Pulmonary Conditions

Pulmonary conditions include, but are not limited to vascularcongestion, mucosal swelling of bronchi and bronchioles, bronchitis,respiratory syncytial virus (RSV) bronchitis, etc. Other pulmonary usesinclude treatment of increases in capillary permeability that furthershrink the available lumen size of an airway. Such increases incapillary permeability occur in allergic rhinitis, common cold;influenza; asthma, acute respiratory distress syndrome, and acute lunginjury. Such conditions can cause alveolar capillary increasedpermeability and capillary changes along the mucosal surface that swellthe mucosa into the lumen. An increase in capillary permeability isknown as one of the main features by which these pathogens aredisseminated inside a host organism through cascade of inflammatorybyproducts and other specific means of induction.

In one embodiment, the invention generally relates to a method fortreatment of a pulmonary condition comprising delivering compositions ofthe present invention as an aerosol having mass medium average diameterpredominantly between 1 to 10μ, produced by an inhaler, jet orultrasonic nebulizer.

d) Other Conditions

The methods and compositions of the present invention may also be usedin other clinical indications for vasoconstriction, such as treating thesubcutaneous epidermal swelling observed along and around the lowereyelids or the venous dilation of hemorrhoids. The present inventionfurther provides compositions formulated to relieve the vascularengorgement associated with dilated vessels of hemorrhoid tissue withless morbidity than epinephrine or phenylephrine used with prior art.Compositions particularly useful for these purposes comprise brimonidineat concentrations of from 0.01% to 0.05%.

The present invention further provides compositions formulated torelieve the vascular engorgement associated with dilated vessels ofpulmonary bronchi and bronchioles, via inhalant vehicle, to relieve moreeffectively than prior art, with less morbidity than epinephrine,norepinephrine, or pseudoephedrine, mucosal swelling and congestionassociated with colds, flu, and other productive cough. Compositionsparticularly useful for these purposes comprise brimonidine atconcentrations of from 0.001% to 0.040%.

In addition, the methods and compositions of the present invention maybe used during endotracheal intubation.

In another embodiment, the invention relates to a method of treatingsore throat, comprising administering locally to a patient in needthereof a selective a-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for a-2 over a-1 adrenergic receptors,or a pharmaceutically acceptable salt thereof, in the absence of asubstantial amount of another therapeutic agent, wherein said selectivea-2 adrenergic receptor agonist is present at a concentration belowabout 0.01% weight by volume.

In a preferred embodiment, the invention generally relates to a methodof scleral whitening without significant rebound hyperemia, comprisingadministering to a patient in need thereof a topical compositioncomprising a selective a-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for a-2 over a-1 adrenergic receptors,or a pharmaceutically acceptable salt thereof, wherein said selectivea-2 adrenergic receptor agonist is present at a concentration belowabout 0.05% weight by volume.

This method allows achieving a more effective scleral whitening (i.e.,whiter shades of scleral color) than possible with prior artcompositions and methods, as a result of more effective vasoconstrictionthat creates sufficient constriction of the capillary bed within thesclera to induce an overall whitening not observed with prior art,allowing for an improved cosmetic appearance.

For the methods of scleral whitening, the preferred a-2 agonist isbrimonidine at a concentration of from about 0.01% to about 0.05%, andmore preferably, from about 0.015% to about 0.02%.

The methods and compositions of the present invention may also be usedto treat noninfectious conjunctival hyperemia (caused, for example, bylack of sleep, consumption of alcohol, or other noninfectious causes).

In another embodiment, the invention generally relates to a method ofreducing redness in an eye, comprising administering to a patient inneed thereof a topical composition comprising a selective a-2 adrenergicreceptor agonist having a binding affinity of 100 fold or greater fora-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable saltthereof, wherein said selective a-2 adrenergic receptor agonist ispresent at a concentration below about 0.05% weight by volume.

In a preferred embodiment, the administering step of the topicalcomposition may be done through the use of a hydrophilic contact lens,wherein the hydrophilic lens comprises a reservoir for retaining thetopical compositions of the present invention.

For the method of reducing redness in an eye, the preferred a-2 agonistis brimonidine at a concentration of from about 0.005% to about 0.015%.

In yet another embodiment, the invention generally relates to a methodfor lightening tissue coloration comprising administering locally to apatient in need thereof a topical composition comprising a selective a-2adrenergic receptor agonist having a binding affinity of 100 fold orgreater for a-2 over a-1 adrenergic receptors, or a pharmaceuticallyacceptable salt thereof, wherein said selective a-2 adrenergic receptoragonist is present at a concentration below about 0.05% weight byvolume.

In a preferred embodiment, methods of the present invention allowadministration of the selective a-2 agonists for approximately at leasta week; for approximately two weeks; for approximately three weeks; forapproximately one month; for approximately two months; for approximatelybetween two months and one year; for approximately one year; and forapproximately longer than one year. It is to be understood that it iswithin a skill in the art to determine the most appropriate time periodof administration.

The low toxicity and low incidence of hyperemia with the compositions ofthe present invention enables their relatively frequent and long termuse. For example, clinical study of brimonidine 0.5% tid for one monthand brimonidine 0.2% bid for one year equate to clinical use forvasoconstriction of sixty times per day and sixteen times per dayrespectively for brimonidine 0.025%, a typical concentration of apreferred embodiment of the present invention. In most cases, ifdesired, treatment can be repeated as often as every two hours, orcommonly once every three to four hours.

In general, low concentrations of vasoconstrictive agents can be appliedfor prolonged periods of time (for example, for several hours) for muchgreater therapeutic index in reaching affected superficial vascularregions. The etiology of conditions that may benefit fromvasoconstrictors is largely due to vascular abnormalities, inflammatorychanges, or other vascular responses to chemical modulation by emotionalchanges (flushing). In addition, systemic absorption is typicallyconsiderably reduced compared to mucous membranes. Facial rosacea, andin particular, acne rosacea have distribution along either side of thenasal bridge, under the eyelids, and frequently includes the lowereyelids.

Thus, for many facial applications of emollients or creams, thecompositions of the present invention offer improved safety and efficacyas compared to higher concentrations of the prior art.

However, in one embodiment, the application time of the compositions ofthe present invention lasts not more than about five minutes. In anotherembodiment, the application time of the compositions of the presentinvention is less than one minute.

Based on the use of such molecules at much higher doses for chronictreatment of glaucoma, the treatment for vasoconstriction can also beused to treat chronic conditions. For example, treatments can berepeated over a period of several months to a year, and most likelyseveral years, as is currently common for glaucoma treatment with thisclass of molecules.

Due to its high safety profile regarding adverse systemic toxicity, thecompositions of the present invention may be used every two hours, ormore commonly, every three to four hours with low incidence ofhyperemia. The concentrations should be optimized for theirvasoconstrictive dose response curve, which may differ from otherdesired clinical effects.

Combination Treatments

In addition to using low doses of highly selective a-2 agonists bythemselves, the invention also provides methods for using these highlyselective a-2 agonists in several combinatorial applications, forexample in combinations with a-1 antagonists and in combinations withantihistamines.

A. Combinations with a-1 Antagonists

a-1 antagonists have been shown to have the property of reducingscotopic and mesopic pupil dilation. a-1 agonists of prior art, such asnaphazoline, tetrahydrozoline, and oxymetazoline, have an undesirableproperty of causing papillary dilation with attendant reduction inquality of vision in a significant percentage of individuals. The highlyselective a-2 agonists of the present invention at the claimedconcentrations do not cause papillary dilations.

The compositions and methods of the present invention may combine highlyselective a-2 agonists, as defined by the present invention, with a-1antagonists and/or selective a-1 antagonists to minimize hyperemia andoptimize the concentration which can be used for maximum reduction ofsympathomimetic induced low light pupil enlargement. This has importantconsequence for improving night vision in people with large pupils andincreased higher order aberrations, or higher order aberrations fromother causes (such as refractive surgery).

Phentolamine is a preferred pharmaceutical agent for such use. Whencombined with the present invention, its use is further optimized.Preferably, when used in combination, the highly selective a-2 agonistsof the present invention are employed in ratios varying from about 0.02%to about 0.05%. Most preferably, the a-1 antagonist is phentolaminemyrsalate, and its concentration is from about 0.01% to about 0.1%.

B. Combinations with Antihistamines

In another embodiment, the invention generally relates to a compositionformulated for treating and/or preventing an allergic response withreduced rebound hyperemia, comprising a selective a-2 adrenergicreceptor agonist having a binding affinity of 100 fold or greater fora-2 over a-1 adrenergic receptors, or a pharmaceutically acceptable saltthereof, and a histamine antagonist, wherein said selective a-2adrenergic receptor agonist is present at a concentration below about0.025% weight by volume.

In another preferred embodiment, the invention generally relates to amethod of treating and/or preventing an allergic response with reducedrebound hyperemia comprising administering to a patient in need thereofthe composition comprising a selective a-2 adrenergic receptor agonisthaving a binding affinity of 100 fold or greater for a-2 over a-1adrenergic receptors, or a pharmaceutically acceptable salt thereof, anda histamine antagonist, wherein said selective a-2 adrenergic receptoragonist is present at a concentration below about 0.025% weight byvolume.

In a preferred embodiment, the a-2 agonist is brimonidine at aconcentration of from about 0.001% to about 0.025% weight by volume; andthe preferred histamine antagonist is selected from the group consistingof loratadine, desloratadine, cetirizine, fexofenadine, acrivastine,ebastine, norastemizole, levocetirizine, and mizolastine.

In a preferred embodiment, the composition for treating and/orpreventing an allergic response with reduced rebound hyperemia is anaerosolized composition.

In a preferred embodiment, the invention generally relates to acomposition consisting essentially of brimonidine and pheniraminemaleate, wherein said brimonidine concentration is from between about0.001% to about 0.025% weight by volume, wherein pH of said compositionis between about 5.5 and about 6.5, and wherein said composition isformulated as an aerosolized composition.

In a preferred embodiment, the invention generally relates to acomposition consisting essentially of brimonidine and a nonsedatingantihistamine, wherein said brimonidine concentration is from betweenabout 0.001% to about 0.025% weight by volume, wherein pH of saidcomposition is between about 5.5 and about 6.5, and wherein saidcomposition is formulated as an aerosolized composition.

Compositions (Formulations)

The compositions of the present invention are preferably formulated fora mammal, and more preferably, for a human.

In one embodiment, the compositions of the present invention are topicalcompositions. In one embodiment, the topical composition is formulatedfor treating and/or preventing an ocular condition.

The topical compositions include, but are not limited to, ocular drops,ocular ointments, gels and creams. They may also include additionalnon-therapeutic components, which include, but are not limited to,preservatives, delivery vehicles, tonicity adjustors, buffers, pHadjustors, antioxidants, and water.

The preservatives include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate, orphenylmercuric nitrate. Vehicles useful in a topical ophthalmiccomposition include, but are not limited to, polyvinyl alcohol,povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethylcellulose, hydroxyethyl cellulose and purified water. Some of thepreferred preservatives include Blink® (Abbott Medical Optics®; activeingredient: polyethylene glycol 400 0.25%) and perborate. It is alsopossible to use a physiological saline solution as a major vehicle.

A tonicity adjustor also can be included, if desired, in a topicalcomposition of the invention. Such a tonicity adjustor can be, withoutlimitation, a salt such as sodium chloride, potassium chloride, mannitolor glycerin, or another pharmaceutically or ophthalmically acceptabletonicity adjustor.

Various buffers and means for adjusting pH can be used to preparetopical compositions of the invention. Such buffers include, but are notlimited to, acetate buffers, citrate buffers, phosphate buffers andborate buffers. It is understood that acids or bases can be used toadjust the pH of the composition as needed. Topically acceptableantioxidants useful in preparing a topical composition include, yet arenot limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

To make the topical compositions of the present invention, one cansimply dilute, using methods known in the art, more concentratedsolutions of selective a-2 agonists. The precise method of carrying outthe dilutions is not critical. Any commonly used diluents, includingpreservatives described above in the application, suitable for topicalsolutions can be used.

In one embodiment, the topical compositions of the present invention areophthalmic compositions. An ophthalmic composition contains anophthalmically acceptable carrier, which can be any carrier that hassubstantially no long term or permanent detrimental effect on the eye towhich it is administered. Examples of ophthalmically acceptable carriersinclude, but are not limited to, water, including distilled or deionizedwater; saline; and other aqueous media.

In another preferred embodiment, said composition is an aerosolizedcomposition. In one embodiment, the aerosolized composition isformulated for treating and/or preventing a pulmonary condition.

It is within a skill in the art to prepare aerosolized compositions ofthe present invention.

The aerosolized compositions of the present invention are generallydelivered via an inhaler, jet nebulizer, or ultrasonic nebulizer whichis able to produce aerosol particles with size of between about 1 and 10μm.

In one embodiment, the selective a-2 agonist may be formulated in about5 ml solution of a quarter normal saline having pH between 5.5 and 6.5,preferably between 5.5 and 6.0.

In a preferred embodiment, the aerosolized composition comprises about0.02% brimonidine in about 5 ml solution, which further comprises about0.225% sodium chloride, and wherein said composition has a pH betweenabout 5.5 and 6.5, preferably between 5.5 and 6.0.

In a preferred embodiment, a pH of the compositions of the presentinvention is less than about 7.0, preferably, between about 5.5 andabout 6.5, more preferably between 5.5 and 6.0.

In another preferred embodiment, the compositions of the presentinvention further include potassium (i.e., K+). The term “potassium”includes, but is not limited to, potassium salt. Preferably, potassiumis potassium chloride.

In another preferred embodiment, the compositions of the presentinvention further include calcium (i.e., Ca²⁺). The term “calcium”includes, but is not limited to, calcium salt. Preferably, calcium iscalcium chloride.

In yet another preferred embodiment, the compositions of the presentinvention comprise nitrous oxide inhibitors. In a preferred embodiment,the nitrous oxide inhibitors are selected from the group consisting ofL-NAME, L-NIL, L-NIO, and L-canavine, or combinations thereof.Preferably, concentration of the nitrous oxide inhibitors is betweenabout 0.005% and about 0.5% weight by volume.

In another embodiment, the compositions of the present invention can beincluded in a pharmaceutically suitable vehicle suitable for oralingestion. Suitable pharmaceutically acceptable carriers include solidfillers or diluents and sterile aqueous or organic solutions. The activecompound will be present in such pharmaceutical compositions in theamounts sufficient to provide the desired dosage in the range asdescribed above.

Pharmaceutical compositions contemplated for use in the practice of thepresent invention can be used in the form of a solid, a solution, anemulsion, a dispersion, a micelle, a liposome, and the like, wherein theresulting composition contains one or more of the active compoundscontemplated for use herein, as active ingredients thereof, in admixturewith an organic or inorganic carrier or excipient suitable for nasal,enteral or parenteral applications. The active ingredients may becompounded, for example, with the usual non-toxic, pharmaceutically andphysiologically acceptable carriers for tablets, pellets, capsules,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, suppositories, solutions, emulsions, suspensions, hard or softcapsules, caplets or syrups or elixirs and any other form suitable foruse. The carriers that can be used include glucose, lactose, gum acacia,gelatin, mannitol, starch paste, magnesium trisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea, medium chainlength triglycerides, dextrans, and other carriers suitable for use inmanufacturing preparations, in solid, semisolid, or liquid form. Inaddition auxiliary, stabilizing, thickening and coloring agents may beused.

In one embodiment, the compositions of the present invention can beadministered locally via an intraocular or periocular implant, which canbe, without limitation, biodegradable or reservoir-based. As usedherein, the term “implant” refers to any material that does notsignificantly migrate from the insertion site following implantation. Animplant can be biodegradable, non-biodegradable, or composed of bothbiodegradable and non-biodegradable materials; a non-biodegradableimplant can include, if desired, a refillable reservoir. Implants usefulfor preventing or alleviating an ocular condition include, for example,patches, particles, sheets, plaques, microcapsules and the like, and canbe of any shape and size compatible with the selected site of insertion,which can be, without limitation, the posterior chamber, anteriorchamber, suprachoroid or subconjunctiva of the eye. It is understoodthat a useful implant generally releases the implanted ophthalmiccomposition at a therapeutically effective dose to the eye of thesubject over an extended period of time. A variety of ocular implantsand extended release formulations suitable for ocular release are wellknown in the art, as described, for example, in U.S. Pat. Nos. 5,869,079and 5,443,505.

The present invention is more fully demonstrated by reference to theaccompanying drawings.

FIG. 1 depicts vasoconstrictive net clinical effectiveness for prior arta-agonists. Vasoconstrictive net clinical effectiveness is calculated bysubtracting each compound's rebound hyperemic dose response curve fromvasoconstrictive dose response curve. The general effectiveness andapproximate optimal concentrations with the least rebound are revealedby the X-Y intersecting dashed lines. There is a slight peak for eachmolecule where its benefit to risk ratio is optimized. The referenceconcentration mark at 0.08% is to the right of the dose response data.

FIG. 2 highlights the key discoveries of the present invention. Itdepicts a plot of vasoconstriction effect versus various concentrationsof brimonidine, a selective a-2 agonist of the present invention.Vasoconstrictive effect when studied at reduced concentrations is shownto have been above its maximum dose response benefit, while intraocularpressure reduction and corneal endothelial cell pump inhibition areshown to have been just at their maximum at about 0.09%. As a result,there is an exponential drop-off in intraocular pressure reduction andendothelial cell pump inhibition just below 0.08%, whilevasoconstrictive effect remains largely unchanged at these lowerconcentrations until much lower concentrations are reached.

It also demonstrates that concentrations of brimonidine of 0.10% andhigher induce a large enough population of a-1 agonists to achieverebound virtually identical to tetrahydrozaline, naphazoline andoxymetazoline; and may contribute an excessive number of a-2 receptorsas well. FIG. 2 demonstrates that highly selective a-2 agonists definedby their binding affinities (K_(i)) for a-2 over a-1 receptors of morethan 100:1, more preferably 500:1, even more preferably 700:1, even morepreferably 1000:1 or greater, and most preferably, 1500:1 or greater,results in an optimized concentration range for optimal vasoconstrictionwithout rebound hyperemia.

FIG. 3 depicts a graphical representation of clinical effectiveness ofthe compositions of the present invention versus prior art compositions.The net effect of this improved vasoconstrictive benefit of a-2predominant receptor activation and reduced rebound is highlighted forbrimonidine in FIG. 3 relative to a-agonist vasoconstrictors in currentclinical use. The potency and reduced morbidity allow for additionalbenefits of the subclass of more highly selective a-2 agonists asdefined by the present invention.

FIG. 4 contains graphical representations of results of Example 1 andwill be explained more fully in the section of the application dealingwith Example 1.

FIGS. 5 A-C demonstrate the unexpected discovery that novel and highlyselective a-2 compositions of the present invention can reversepre-induced rebound hyperemia of general alpha agonists.

FIG. 5A is a baseline visual appearance of two eyes of a patient with anocular condition.

FIG. 5B depicts a visual appearance of the right eye of the patientafter being treated with a prior art composition comprising VISINEOriginal® (Johnson & Johnson's registered trademark; active ingredient:tetrahydrozoline HCL 0.05%) and the induction of rebound hyperemia, andthe visual appearance of the left eye of the patient after being treatedsimultaneously with a composition of the present invention comprisingbrimonidine at 0.015%.

FIG. 5C depicts a visual appearance of the right eye of the patientafter then being treated with the novel composition of the presentinvention comprising brimonidine at 0.015%, reversing the VISINEOriginal® induced rebound hyperemia, and a visual appearance of the lefteye of the patient after being treated simultaneously with an additionaldrop of the composition of the present invention comprising brimonidineat 0.015%.

FIG. 6 depicts a graphical representation of a finding of the presentinvention that an increased rebound hyperemia begins at around 0.03% forbrimonidine. It thus demonstrates that the net effectiveness ofbrimonidine as a decongestant is greatest between about 0.01% and about0.03%; preferably, between about 0.012% and about 0.02%

The following Examples are provided solely for illustrative purposes andare not meant to limit the invention in any way.

EXAMPLES Example 1

In this Example, a patient was treated with brimonidine at claimedconcentrations and prior art compositions of tetrahydrozoline,oxymetazoline and naphazoline.

The results clearly demonstrate significant scleral whiteningbrightening effects of treatment with brimonidine as compared withtreatment with prior art compositions.

The results are shown in FIGS. 4A through 4E.

FIG. 4A shows the base line for both eyes.

FIG. 4B shows a comparison after 180 minutes, where the right eye hasbeen treated with tetrahydrozoline at 0.05% and the left eye was treatedwith brimonidine at 0.01%

FIG. 4C shows a comparison four hours after baseline (FIG. 4A), wherethe right eye has been treated with oxymetazoline at 0.025% and the lefteye was treated with brimonidine at 0.02%

FIG. 4D shows a comparison where after a further four hours, the righteye has been treated with naphazoline at 0.033%; and the left eye wastreated with brimonidine at 0.02%.

FIG. 4E shows the effect of brimonidine at 0.033% on the left eye only,4 hrs after the effect shown in FIG. 4D (showing the third applicationto be without rebound hyperemia).

The effectiveness in most clinical situations is likely to be evengreater, since baseline redness was at 4/4 for this test. In an averageclinical situation, baseline redness is at 1-1.5/4.

Accordingly, the results show that compositions of the present inventionmay be used every three to four hours with low incidence of hyperemia.

Example 2 Lasik Prophylaxis

Baseline:

Treatment of 200 patients via the Intralase femtosecond laser with nopretreatment for vasoconstriction—significant postoperative hyperemiaand conjunctival hemorrhage with @ 15% petichial or larger hemorrhagewhen patients were seen postoperative day 1.25% 1+(14) hyperemia firsthour +; 50% 2.5+ hyperemia first how +; 25% 3+ hyperemia first hour +.Flap dislocation rate: <0.1%.

Treatment Group 1:

Naphcon-A® (Alcon, Inc; active ingredients: naphazoline hydrochloride0.25% and pheniramine maleate 0.3%; preserved with benzalkoniurnmchloride) was used on a second group of 50 patients (85 procedures), 12%petichial or larger hemorrhage. 35% 1+ hyperemia; 35% 2+ hyperemia; 15%2.5+ hyperemia; 15% 3+ hyperemia. Some clinical benefit noted. Flapdislocation rate: <0.1%.

Treatment Group 2:

Brimonidine 0.2%, used off label, has been reported to cause flapdislocation rates of 5-10% and is currently not indicated norrecommended for this purpose.

Brimonidine 0.02% on 16 eyes, with no adverse effects or significantchange in intraocular pressure, mean blood pressure or pulse noted.

Treatment Group 3:

Brimonidine 0.02% applied topically I-ii gtts per eye, 10-20 minutespreoperatively to an initial trial of 10 patients (100 eyes). <5%petichial or larger hemorrhage; 75% 1+ hyperemia or less; 20% 2+hyperemia; 5% 2.5+ hyperemia, flap dislocation rate just under 1%.

This group has been expanded to include over 500 eyes with similarresults. A markedly different white quiet eye is noted in most patients,with no or only trace hyperemia found in the majority of the I+ or lesshyperemic group. Flap dislocation rate remains just under 1% with mostof these mild striae as opposed to actual dislocation, similar to thatfound with Group 0 and 1.

Cosmetically, the patients are much improved from day 1 vs. novasoconstrictor and vs. Naphcon-A. No adverse cardiovascular eventsoccurred. No significant allergic reactions have been found.

Example 3

0.03% Brimonidine Nasal Spray: 0.9% saline vehicle used and nasal sprayadministered to patient with nasal congestion. This was repeated for oneweek without rebound. Complete relief for 3-5 hours was reached perapplication for treatment of moderate nasal congestion thought to beallergic in nature. Repeat applications×four hours without rebound.Patient population for this test limited to n of 1.

The proper dose response range can be tested with no more than routineexperimentation.

Example 4

Eighteen patients having a red eye condition were treated with acomposition of the present invention (i.e., brimonidine at 0.018%) andwith VISINE Original®. Three patients withdrew from the study prior tocompletion.

The patients were assigned “cumulative red scores”, prior to eachadministration (as baseline) and then 10 min after each dose, bydividing the bulbar conjunctiva into six sectors, each scored with agrade 1-3 score and the total cumulative score. In terms of initialefficacy of the active vs. VISINE Original® the patients were calculatedto have 68.71% reduction in redness score after administration of asingle dose of brimonidine at 0.018%, and 31.06% reduction in rednessscore after administration of VISINE Original® after a singleapplication.

Rebound hyperemia after one dose occurred only in 6.6% afteradministration of brimonidine at 0.05% (1 of 15) and in 26.6% afteradministration of VISINE Original®.

The three week scores also demonstrated advantages of the compositionsof the present invention: after administration of brimonidine at 0.018%,the average redness count went down from 10.3 to 1.6; afteradministration of VISINE Original®, the average redness count went downfrom 8.8 to 2.5. However, it is possible that due to the length of thestudy and inadvertent dilution of preservative in formulation,contamination of the brimonidine 0.018% composition may have occurredtowards the end.

Example 5

Seven patients with chronic red eyes were treated as follows: one eyewas treated with extreme low dose (eld) brimonidine at 0.015% and theother eye was treated with Naphcon-A®. The treatment was through dropstwice a day for three to five weeks. At the end, patient satisfactionassessment was conducted.

All patients reported reduced redness on eld brimonidine.

42% preferred eld brimonidine.

0% preferred Naphcon-A®.

1. A method of reducing activation of a-1 adrenergic receptorscomprising administering to a patient having a nasal congestion, anocular or pulmonary condition a selective a-2 adrenergic receptoragonist having a binding affinity of 100 fold or greater for a-2 overa-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof,wherein said selective a-2 adrenergic receptor agonist is present at aconcentration below about 0.05% weight by volume.
 2. The method of claim1, wherein said binding affinity is about 500 fold or greater for a-2over a-1 adrenergic receptors.
 3. The method of claim 1, wherein saida-2 adrenergic receptor agonist is present at a concentration betweenabout 0.001% to about 0.025% weight by volume.
 4. The method of claim 1,wherein said selective a-2 adrenergic receptor agonist is selected fromthe group consisting of apraclonidine, mivazerol, clonidine,brimonidine, alpha methyl dopa, guanfacine, dexemeditomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.5. A method of reducing activation of a-1 adrenergic receptorscomprising administering to a patient having an ocular condition acomposition comprising brimonidine, wherein said brimonidineconcentration is from between about 0.001% to about 0.025% weight byvolume.
 6. A method of reducing activation of a-1 adrenergic receptorscomprising topically administering to a patient having an ocularcondition a composition consisting essentially of brimonidine intoocular tissue, wherein pH of said composition is between about 5.5 andabout 6.5, wherein said brimonidine concentration is between about0.001% and about 0.025% weight by volume and wherein said composition isformulated as an ocular drop.
 7. The method of claim 6, wherein saidcomposition is topically administered within about 24 hours after aLasik surgery on said patient.
 8. A method of reducing activation of a-1adrenergic receptors comprising administering to a patient having anasal congestion, an ocular or pulmonary condition a selective a-2adrenergic receptor agonist having a binding affinity of 100 fold orgreater for a-2 over a-1 adrenergic receptors, or a pharmaceuticallyacceptable salt thereof, wherein said selective a-2 adrenergic receptoragonist is present at a concentration below about 0.05% weight byvolume, whereby the reduced a-1 adrenergic receptor activation is belowthe ED₅₀ for a-1 induced vasoconstriction larger arteries and/orarterioles.
 9. A composition for reducing activation of a-1 adrenergicreceptors comprising a selective a-2 adrenergic receptor agonist havinga binding affinity of 100 fold or greater for a-2 over a-1 adrenergicreceptors, or a pharmaceutically acceptable salt thereof, wherein saidselective a-2 adrenergic receptor agonist is present at a concentrationbelow about 0.05% weight by volume.
 10. The composition according toclaim 9, wherein said composition consists essentially of brimonidine,wherein pH of said composition is between about 5.5 and about 6.5,wherein said brimonidine concentration is between about 0.001% and about0.025% weight by volume and wherein said composition is formulated as anocular drop.